Fibroblast growth factor 21 protects the heart from angiotensin II-induced cardiac hypertrophy and dysfunction via SIRT1.

This study investigated the mechanism through which fibroblast growth factor 21 (FGF21) protects against angiotensin II (Ang II)-induced cardiac hypertrophy and dysfunction. Male silent information regulator 1 (SIRT1) flox/flox and cardiomyocyte-specific inducible SIRT1 knockout mice (SIRT1-iKO) were generated and treated with Ang II (1.1 mg/kg/day for 4 weeks) at the age of 8-12-week-old. FGF21 treatment [2.5 mg/kg/day for 4 weeks by intraperitoneal (i.p.) injection] was initiated at the same time as the Ang II infusion. For in vitro studies, neonatal rat cardiomyocytes (NRCMs), H9c2 rat cardiomyocytes and isolated adult mouse cardiomyocytes were treated with Ang II (1 μM) and FGF21 (20 nM) for 24 h with or without SIRT1 silencing. FGF21 treatment significantly attenuated Ang II-induced cardiac hypertrophy and dysfunction. SIRT1 knockout abolished the ability of FGF21 to prevent Ang II-induced cardiac hypertrophy, fibrosis, and apoptosis, without affecting the beneficial effects of FGF21 in Ang II-induced hypertension, and did not influence the hypertension itself. FGF21 markedly increased the deacetylase activity of SIRT1 and promoted the interaction of SIRT1 with liver kinase B1 (LKB1) and forkhead box protein O1 (FoxO1), resulting in decreased acetylation of these SIRT1 target proteins. Consequently, FGF21 promoted the activation of the LKB1 target adenosine monophosphate-activated protein kinase (AMPK) and altered the transcriptional activity of FoxO1 on its downstream target genes catalase (Cat), MnSOD (Sod2), and Bim, resulting in reduced reactive oxygen species (ROS) accumulation and cardiomyocyte apoptosis. FGF21 improves cardiac function and alleviates Ang II-induced cardiac hypertrophy in a SIRT1-dependent manner.

Li S ，Zhu Z ，Xue M ，Yi X ，Liang J ，Niu C ，Chen G ，Shen Y ，Zhang H ，Zheng J ，Zhao C ，Liang Y ，Cong W ，Wang Y ，Jin L ... -  《-》

SIRT2 Acts as a Cardioprotective Deacetylase in Pathological Cardiac Hypertrophy.

Pathological cardiac hypertrophy induced by stresses such as aging and neurohumoral activation is an independent risk factor for heart failure and is considered a target for the treatment of heart failure. However, the mechanisms underlying pathological cardiac hypertrophy remain largely unknown. We aimed to investigate the roles of SIRT2 in aging-related and angiotensin II (Ang II)-induced pathological cardiac hypertrophy. Male C57BL/6J wild-type and Sirt2 knockout mice were subjected to the investigation of aging-related cardiac hypertrophy. Cardiac hypertrophy was also induced by Ang II (1.3 mg/kg/d for 4 weeks) in male C57BL/6J Sirt2 knockout mice, cardiac-specific SIRT2 transgenic (SIRT2-Tg) mice, and their respective littermates (8 to ≈12 weeks old). Metformin (200 mg/kg/d) was used to treat wild-type and Sirt2 knockout mice infused with Ang II. Cardiac hypertrophy, fibrosis, and cardiac function were examined in these mice. SIRT2 protein expression levels were downregulated in hypertrophic hearts from mice. Sirt2 knockout markedly exaggerated cardiac hypertrophy and fibrosis and decreased cardiac ejection fraction and fractional shortening in aged (24-month-old) mice and Ang II-infused mice. Conversely, cardiac-specific SIRT2 overexpression protected the hearts against Ang II-induced cardiac hypertrophy and fibrosis and rescued cardiac function. Mechanistically, SIRT2 maintained the activity of AMP-activated protein kinase (AMPK) in aged and Ang II-induced hypertrophic hearts in vivo as well as in cardiomyocytes in vitro. We identified the liver kinase B1 (LKB1), the major upstream kinase of AMPK, as the direct target of SIRT2. SIRT2 bound to LKB1 and deacetylated it at lysine 48, which promoted the phosphorylation of LKB1 and the subsequent activation of LKB1-AMPK signaling. Remarkably, the loss of SIRT2 blunted the response of AMPK to metformin treatment in mice infused with Ang II and repressed the metformin-mediated reduction of cardiac hypertrophy and protection of cardiac function. SIRT2 promotes AMPK activation by deacetylating the kinase LKB1. Loss of SIRT2 reduces AMPK activation, promotes aging-related and Ang II-induced cardiac hypertrophy, and blunts metformin-mediated cardioprotective effects. These findings indicate that SIRT2 will be a potential target for therapeutic interventions in aging- and stress-induced cardiac hypertrophy.

Tang X ，Chen XF ，Wang NY ，Wang XM ，Liang ST ，Zheng W ，Lu YB ，Zhao X ，Hao DL ，Zhang ZQ ，Zou MH ，Liu DP ，Chen HZ ... -  《-》

Cardioprotective effects of fibroblast growth factor 21 against doxorubicin-induced toxicity via the SIRT1/LKB1/AMPK pathway.

Wang S ，Wang Y ，Zhang Z ，Liu Q ，Gu J ... -  《Cell Death & Disease》

Ginkgolide B Protects Cardiomyocytes from Angiotensin II-Induced Hypertrophy via Regulation of Autophagy through SIRT1-FoxO1.

Ginkgolide B (GB) is an active ingredient extracted from Ginkgo biloba leaves. However, the effects of GB on cardiac hypertrophy remain unclear. The study is aimed at determining whether GB could alleviate cardiac hypertrophy and exploring its underlying molecular mechanism. Rat cardiomyocyte cell line H9c2 cells were pretreated with GB and incubated with angiotensin II (Ang II) to simulate an in vitro cardiac hypertrophy model. Cell viability, cell size, hypertrophy markers, and autophagy were determined in H9c2 cells after Ang II treatment. Proteins involved in autophagy and the SIRT1 pathway were determined by western blot. Our data demonstrated that GB attenuated Ang II-induced cardiac hypertrophy and reduced the mRNA expressions of hypertrophy marker, atrial natriuretic peptide (ANP), and β-myosin heavy chain (β-MHC). GB further increased Ang II-induced autophagy in H9c2 cells and modulated expressions of autophagy-related proteins Beclin1 and P62. Modulation of autophagy using autophagy inhibitor 3-methyladenine (3-MA) could abrogate GB-downregulated transcription of NPPA. We then showed that GB attenuated Ang II-induced oxidative stress and reduction in SIRT1 and FoxO1 protein expression. Finally, the effect of GB on autophagy and cardiac hypertrophy could be reversed by SIRT1 inhibitor EX-527. GB inhibits Ang II-induced cardiac hypertrophy by enhancing autophagy via the SIRT1-FoxO1 signaling pathway and might be a potential agent in treating pathological cardiac hypertrophy.

Jiang Q ，Lu M ，Li J ，Zhu Z ... -  《-》

CD38 promotes angiotensin II-induced cardiac hypertrophy.

Cardiac hypertrophy is an early hallmark during the clinical course of heart failure and regulated by various signalling pathways. Recently, we observed that mouse embryonic fibroblasts from CD38 knockout mice were significantly resistant to oxidative stress such as H2 O2 -induced injury and hypoxia/reoxygenation-induced injury. In addition, we also found that CD38 knockout mice protected heart from ischaemia reperfusion injury through activating SIRT1/FOXOs-mediated antioxidative stress pathway. However, the role of CD38 in cardiac hypertrophy is not explored. Here, we investigated the roles and mechanisms of CD38 in angiotensin II (Ang-II)-induced cardiac hypertrophy. Following 14 days of Ang-II infusion with osmotic mini-pumps, a comparable hypertension was generated in both of CD38 knockout and wild-type mice. However, the cardiac hypertrophy and fibrosis were much more severe in wild-type mice compared with CD38 knockout mice. Consistently, RNAi-induced knockdown of CD38 decreased the gene expressions of atrial natriuretic factor (ANF) and brain natriuretic peptide (BNP) and reactive oxygen species generation in Ang-II-stimulated H9c2 cells. In addition, the expression of SIRT3 was elevated in CD38 knockdown H9c2 cells, in which SIRT3 may further activate the FOXO3 antioxidant pathway. The intracellular Ca2+ release induced by Ang-II markedly decreased in CD38 knockdown H9c2 cells, which might be associated with the decrease of nuclear translocation of NFATc4 and inhibition of ERK/AKT phosphorylation. We concluded that CD38 plays an essential role in cardiac hypertrophy probably via inhibition of SIRT3 expression and activation of Ca2+ -NFAT signalling pathway. Thus, CD38 may be a novel target for treating cardiac hypertrophy.

Guan XH ，Hong X ，Zhao N ，Liu XH ，Xiao YF ，Chen TT ，Deng LB ，Wang XL ，Wang JB ，Ji GJ ，Fu M ，Deng KY ，Xin HB ... -  《-》